Immune accessibility of mtDNA in tumors: mechanical adaptation, spatial exposure, sensing topology, and immune outcomes

Abstract Physical states in solid tumors, including extracellular matrix stiffening, solid compression, spatial confinement, tissue fluidization, and viscoelastic abnormalities, can influence mitochondrial adaptation to structural and energetic loads by reshaping cell adhesion, metabolism, mitochondrial dynamics, and quality control. However, mechanical abnormalities do not necessarily cause mitochondrial DNA (mtDNA) release, and changes in mitochondrial morphology, redox state, or metabolism do not constitute direct evidence of mtDNA exposure. When mitochondrial damage can no longer be adequately repaired, cleared, or contained, barrier failure or alternative transport processes may displace mtDNA from its normal mitochondrial confinement. Once displaced, mtDNA can occupy distinct cytosolic, vesicular, extracellular, or mitochondria-associated states that differ in their accessibility, persistence, and potential for immune sensing. Here, we define this spatial exposure of mtDNA as “immune accessibility” and distinguish it from the nucleic acid-sensing capacity of tumor and host cells. The immune effects of accessible mtDNA depend on its molecular state, mode of delivery, recipient cell, receptor compartment, pathway integrity, and signal duration. Accordingly, mtDNA exposure can promote interferon responses and cytotoxic immunity or instead favor autophagy, immune checkpoint feedback, and myeloid suppression. Direct evidence that fully links tissue mechanics, mtDNA exposure, and immune sensing currently remains largely limited to specific models of tissue fluidization. Accordingly, this review aims to integrate current evidence within an analytical framework of “mechanical adaptation–mtDNA immune accessibility–sensing topology–immune output” and to distinguish therapeutic states characterized by insufficient mtDNA accessibility, impaired sensing competence, or chronic maladaptive signaling. Such a framework may help identify the limiting or redirecting step of the mtDNA immune axis and guide context-dependent DNA-sensing interventions.